Alternative titles; symbols
HGNC Approved Gene Symbol: H3-3B
Cytogenetic location: 17q25.1 Genomic coordinates (GRCh38) : 17:75,776,434-75,779,779 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.1 | Bryant-Li-Bhoj neurodevelopmental syndrome 2 | 619721 | Autosomal dominant | 3 |
Histones are the basic nuclear proteins responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Five classes of histone genes have been reported, all of which are involved in chromosome structure. Some classes are expressed only during S phase, while others are replication independent. The latter are referred to as replacement histones and are expressed in quiescent or terminally differentiated cells. H3.3 is a replacement histone that is encoded by 2 distinct replication-independent genes, H3.3A (H3F3A; 601128) and H3.3B (H3F3B). The proteins encoded by the H3.3A and H3.3B genes are identical (Albig et al., 1995).
For additional background information on histones, histone gene clusters, and the H3 histone family, see HIST1H3A (602810).
Albig et al. (1995) used a histone H1 probe to identify a full-length cDNA, designated H3.3B by them, from a human testicular library. The amino acid sequence of H3.3B is identical to that of H3.3A, as well as to the amino acid sequences of H3.3 homologs in other species, including Drosophila. However, the nucleotide sequences of H3.3A and H3.3B differ substantially, especially in the 5-prime and 3-prime UTRs. Northern blot analysis detected 1.8- and 1.4-kb mRNAs, which differ due to alternative use of polyadenylation signals, in RNA from testis and the HEK293 embryonal kidney tumor cell line.
Using an RNase protections assay, Witt et al. (1997) showed variable expression of 1.4- and 1.8-kb H3.3B transcripts in human tissues and cell lines, with the 1.8-kb transcript predominating. They reported that H3.3a was basally expressed in mouse testis, whereas H3.3b was expressed in a stage-specific manner.
Using Northern blot analysis, Frank et al. (2003) assayed for expression of the replacement histones H3.3A and H3.3B and the cell cycle-dependent histone H3/m (HIST2H3C; 142780) in human tissues and cell lines. All 6 cell lines expressed H3.3A, H3.3B, and H3/m at high levels. Conversely, fetal liver predominantly expressed H3/m, likely due to its rapid cell growth, whereas adult liver, kidney, and heart predominantly expressed H3.3A and H3.3B. The H3.3B transcript was detected at 1.4 and 1.8 kb.
Albig et al. (1995) isolated the H3.3B gene and found that it spans approximately 2.5 kb. It has 4 exons, the first of which is noncoding, and exhibits features characteristic of a histone H3.3 gene.
Witt et al. (1997) identified 6 CCAAT boxes, a conserved functional octamer element, a CRE/TRE element, and a TATA box within the proximal promoter region of the H3.3B gene.
Frank et al. (2003) stated that the 3-prime end of the H3.3B gene contains 3 transcriptional termination signals.
Albig et al. (1995) mapped the H3F3B gene by fluorescence in situ hybridization to chromosome 17q25.
See H3F3A (601128) for functional information on H3.3 histone.
See HIST1H3A (602810) for functional information on the H3 histone family.
Somatic Mutations
Behjati et al. (2013) reported exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases (95%) of chondroblastoma, Behjati et al. (2013) found K36M alterations predominantly encoded by H3F3B, which is 1 of 2 genes for histone H3.3. In contrast, in 92% (49 of 53) of giant cell tumors of bone, Behjati et al. (2013) found histone H3.3 alterations exclusively in H3F3A (601128), leading to G34W or, in 1 case, G34L alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported H3F3A mutations encoding K27M and G34R or G34V alterations in childhood brain tumors, a picture of tumor type specificity for histone H3.3 driver alterations emerged, indicating that histone H3.3 residues, mutations, and genes have distinct functions.
Bryant-Li-Bhoj Neurodevelopmental Syndrome 2
In 13 unrelated patients with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; 619721), Bryant et al. (2020) identified de novo heterozygous mutations in the H3F3B gene (see, e.g., 601058.0001-601058.0004). The mutations, which were found by whole-exome or genome sequencing, occurred throughout the gene. All but 1 were missense variants, and all were absent from the gnomAD database. In vitro studies of lymphoblasts or fibroblasts derived from a subset of patients showed that the distribution of posttranslational modification (PTM) histone abundances was similar to controls. The overall histone PTM variation was slightly increased in controls compared to patients. Nonetheless, some histone PTMs were altered in patients compared to controls. The findings suggested that mutant histones can be incorporated into the nucleosome and cause local deregulation of the chromatin state with modest alterations in the control of histone modification. This could affect multiple histone functions, including gene expression, chromatin stability, DNA damage repair, and differentiation. RNA sequencing of a subset of pooled patient cells showed upregulation of genes involved in mitosis, and in vitro studies of pooled patient fibroblast lines showed increased cellular proliferation compared to controls; viability of patient cells was similar to controls. In silico molecular modeling of the mutations suggested 3 broad scenarios for the variants' impact: disruption of H3.3 DNA binding; disrupted formation of the histone octamer or binding with other histones; and disruption of histone-protein binding to chaperones or other interacting proteins. There were no genotype/phenotype correlations. None of the patients developed cancer.
In 6 unrelated patients with BRYLIB2, Okur et al. (2021) identified 6 different de novo heterozygous mutations at highly conserved residues in the H3F3B gene (see, e.g., 601058.0001 and 601058.0005). The mutations, which were found by exome sequencing, were absent from the gnomAD database. Expression of a subset of variants in HEK293 cells showed that some resulted in decreased protein levels. The mutant proteins localized normally to the nucleus. Molecular modeling suggested that some, but not all, mutations might alter the PTMs of histone H3.3. The possible molecular pathomechanism of other mutations was unclear.
Jang et al. (2015) reported that deletion of H3f3a or H3f3b in mice had no apparent deleterious impact on phenotype or fertility. However, knockout of both genes (H3.3 DKO) led to developmental retardation and embryonic lethality. H3.3 DKO embryos showed reduced cell proliferation and increased cell death. Embryonic stem cells from H3.3 DKO mice had mitotic defects. Growth retardation could be rescued by deletion of p53 (TP53; 191170). RNA sequencing analysis revealed that p53 -/- H3.3 DKO embryos had only limited changes to the transcriptome. H3.3 DKO mouse embryonic fibroblasts lacking p53 proliferated but showed mitotic abnormalities associated with defects in chromosomal heterochromatic structures at telomeres, centromeres, and pericentromeric regions, as well as genome instability. Karyotypic abnormalities and DNA damage in H3.3 DKO mice led to p53 pathway activation. Jang et al. (2015) concluded that H3.3 supports chromosomal heterochromatic structures, thus maintaining genome integrity during mammalian development.
In a 10-year-old boy (patient 34) with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; 619721) Bryant et al. (2020) identified a de novo heterozygous c.25C-T transition (c.25C-T, NM_005324.4) in the H3F3B gene, resulting in an arg9-to-cys (R9C) substitution in the nuclear localization signal. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The authors noted that this mutation would be described as ARG8CYS (R8C) according to standard histone nomenclature, which omits numbering the initiator methionine. Functional studies of the variant were not performed. The patient had global developmental delay, hypotonia, and dysmorphic features.
In a 33-year-old woman (patient 6) with BRYLIB2, Okur et al. (2021) identified a de novo heterozygous R9C mutation at a conserved residue in the H3F3B gene. These authors stated that the substitution occurred in the core histone H3.3 domain. Functional studies were not performed, but molecular modeling predicted that it would alter posttranslational modifications of the protein. The patient had global developmental delay, short stature, seizures, hypothyroidism, type I diabetes mellitus, and dysmorphic features.
In a 5-year-old girl (patient 37) with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; 619721), Bryant et al. (2020) identified a de novo heterozygous c.88G-C transversion (c.88G-C, NM_005324.4) in the H3F3B gene, resulting in an ala30-to-pro (A30P) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The authors noted that this mutation would be described as ALA29PRO (A29P) according to standard histone nomenclature, which omits numbering the initiator methionine. In vitro studies showed that the A30P mutation resulted in notable dysregulation of posttranslational modification (PTM) compared to controls. The patient had global developmental delay, inability to walk or speak, and early-onset seizures.
In 2 unrelated patients (patients 43 and 44) with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; 619721), Bryant et al. (2020) identified a de novo heterozygous c.365C-G transversion (c.365C-G, NM_005324.4) in the H3F3B gene, resulting in a pro122-to-arg (P122R) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The authors noted that this mutation would be described as PRO121ARG (P121R) according to standard histone nomenclature, which omits numbering the initiator methionine. In vitro studies of pooled patient cells suggested that the mutation caused altered posttranslational modifications of the protein. The patients, who were 10 and 18 years of age, had global developmental delay, early-onset severe seizures, and spasticity. Neither could walk or speak.
In a 4-year-old girl (patient 45) with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; 619721), Bryant et al. (2020) identified a de novo heterozygous c.377A-G transition (c.377A-G, NM_005324.4) in the H3F3B gene, resulting in a gln126-to-arg (Q126R) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The authors noted that this mutation would be described as GLN125ARG (Q125R) according to standard histone nomenclature, which omits numbering the initiator methionine. Functional studies of variant were not performed, but it was predicted to alter complex formation. The patient had global developmental delay, hypotonia, and dysmorphic features.
In a 5-year-old boy (patient 9) with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; 619721), Okur et al. (2021) identified a de novo heterozygous c.155T-A transversion (c.155T-A, NM_005324.5) in the H3F3B gene, resulting in an ile52-to-asn (I52N) substitution at a conserved residue in the core histone H3.3 domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Transfection of the mutation into HEK293 cells showed that it caused reduced protein levels compared to controls. Molecular modeling predicted that it would not have an effect on posttranslational modification. The patient had global developmental delay, hypotonia, and seizures.
Albig, W., Bramlage, B., Gruber, K., Klobeck, H.-G., Kunz, J., Doenecke, D. The human replacement histone H3.3B gene (H3F3B). Genomics 30: 264-272, 1995. [PubMed: 8586426] [Full Text: https://doi.org/10.1006/geno.1995.9878]
Behjati, S., Tarpey, P. S., Presneau, N., Scheipl, S., Pillay, N., Van Loo, P., Wedge, D. C., Cooke, S. L., Gundem, G., Davies, H., Nik-Zainal, S., Martin, S., and 17 others. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nature Genet. 45: 1479-1482, 2013. Note: Erratum: Nature Genet. 46: 316 only, 2014. [PubMed: 24162739] [Full Text: https://doi.org/10.1038/ng.2814]
Bryant, L., Li, D., Cox, S. G., Marchione, D., Joiner, E. F., Wilson, K., Janssen, K., Lee, P., March, M. E., Nair, D., Sherr, E., Fregeau, B., and 119 others. Histone H3.3 beyond cancer: germline mutations in histone 3 family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients. Sci. Adv. 6: eabc9207, 2020. [PubMed: 33268356] [Full Text: https://doi.org/10.1126/sciadv.abc9207]
Frank, D., Doenecke, D., Albig, W. Differential expression of human replacement and cell cycle dependent H3 histone genes. Gene 312: 135-143, 2003. [PubMed: 12909349] [Full Text: https://doi.org/10.1016/s0378-1119(03)00609-7]
Jang, C.-W., Shibata, Y., Starmer, J., Yee, D., Magnuson, T. Histone H3.3 maintains genome integrity during mammalian development. Genes Dev. 29: 1377-1392, 2015. [PubMed: 26159997] [Full Text: https://doi.org/10.1101/gad.264150.115]
Okur, V., Chen, Z., Vossaert, L., Peacock, S., Rosenfeld, J., Zhao, L., Du, H., Calamaro, E., Gerard, A., Zhao, S., Kelsay, J., Lahr, A., and 26 others. De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities. NPJ Genom. Med. 6: 104, 2021. [PubMed: 34876591] [Full Text: https://doi.org/10.1038/s41525-021-00268-8]
Witt, O., Albig, W., Doenecke, D. Transcriptional regulation of the human replacement histone gene H3.3B. FEBS Lett. 408: 255-260, 1997. [PubMed: 9188772] [Full Text: https://doi.org/10.1016/s0014-5793(97)00436-5]